This Program Project is conceived as a concerted effort to investigate some keystone issues in evolutionary genetics. The Project formulates a multi- level research program that utilized Drosophila as a model system. The main objectives are as follows: (1) To test "molecular evolutionary clock" by cloning the superoxide dismutase (SOD gene region in a number of dipterans diverged over the las 80 million years and compare it with the SOD of humans and other organisms to ascertain whether this gene has experienced an accelerated evolution in the mammals, as has been claimed. (2) To sequence the SOD region in a large number of Drosophila melanogaster from four geographic regions to certain levels of genetic variation within and between populations. The SOD gene is particularly significant because of its apparent involvement in resistance to radiation and chemical agents, as well as aging. (3) To sequence four other gene regions (Gpdh, Adh, Xdh, and Ddc) in the 15 dipterans, and to sequence Sod i populations of Drosophila stimulants and D willistoni, in order to test the conclusions derived from the SOD results in D. melanogaster. (4) To examine theoretically and empirically the consequences of varying combinations of age-specific and density-dependent selection. (5) To determine the various physiological mechanisms that respond to age- specific or density-specific and density-dependent natural selection. This research program is highly relevant to advance our fundamental understanding of genetic disease and again among other health problems, for which model systems are critical. The Program Project consists of a core and five separate component projects, each of which will be led two or three of the five P>I>s in combinations that vary from one to another component. The components are highly interdependent conceptually, in experimental approach, and in the sharing of common facilities.